Skin substitutes have been developed to promote regeneration of the dermis in deep skin wounds. The main limitations of these products include their susceptibility to infection, lengthy time for blood vessel growth, and being prone to shearing from the wound site. Our long-term goals are to improve these technologies to promote faster and better "scarless" healing, more specifically by expediting blood vessel growth into the skin substitute, as this is a rate-limiting step before the wound can be definitely closed by an epidermal graft. The chemokine SDF-1 is a known chemotactic agent that binds the receptor CXCR4 expressed on many blood-borne immune cells as well as several types of progenitor and stem cells. Recent evidence suggests that, at higher concentrations, SDF-1 can also repel inflammatory cells via CXCR4. Thus, SDF- 1 may in principle perform dual functions: (a) modulate the local inflammatory response, and (b) promote the recruitment of circulating bone marrow-derived stem cells and endothelial progenitors, both of which may be beneficial to wound healing. We hypothesize that local application of exogenous SDF-1 can improve skin wound healing by altering the dynamics of recruitment of CXCR4-expressing cells, including inflammatory cells, endothelial progenitors, and other types of stem/progenitor cells. In the proposed studies, we wish to further characterize the effects of SDF-1 on wound healing, as well as elucidate the impact of chemotactic vs. repellent effects of SDF-1 on the dynamics of recruitment of cells expressing CXCR4 in the wound site. Our specific aims are: (1) To test different doses and schedules of administration of SDF-1 on the dynamics of the inflammatory and wound healing responses, (2) to characterize the effects of SDF-1 on the migration of circulating bone marrow-derived cells into the scaffold material and wound site, and (3) to characterize the effects of SDF-1 on angiogenesis and leukocyte-endothelium interactions in the wound site. The proposed studies will elucidate the potential of SDF-1 to improve wound healing, and provide mechanistic cues (i.e. inflammation reduction and/or stem cell recruitment). Since SDF-1 is a stable peptide with good shelf-life, these studies will lead the way to the next generation of wound dressings and skin substitutes that help wounds heal faster, which could be tested and optimized in a larger and more clinically relevant animal model (e.g. pig), as well as humans. PUBLIC HEALTH RELEVANCE: Slow- and non-healing wounds severely burden the US healthcare system. The goal of this project is to develop skin wound healing scaffolds that promote faster and better "scar"-less healing. These studies will lead the way to the next generation of wound dressings and skin substitutes that help wounds heal faster, which could be tested and optimized in a larger and more clinically relevant animal model (e.g. pig), as well as in humans.